Receptor tyrosine kinases comprise a large family of transmembrane receptors which are comprised of an extracellular ligand-binding domain and an intracellular tyrosine-kinase domain responsible for mediating receptor activity. The receptor tyrosine kinases are involved in a variety of normal cellular responses which include proliferation, alterations in gene expression, and changes in cell shape.
The binding of ligand to its cognate receptor induces the formation of receptor dimers leading to activation of receptor kinase activity. The activation of kinase activity results in phosphorylation of multiple cellular substrates involved in the cascade of events leading to cellular responses such as cell proliferation.
Genetic alterations in growth factor mediated signalling pathways have been linked to a number of different diseases, including human cancer. For example, the normal homologs of many oncogenes have been found to encode growth factors or growth factor receptors. This is illustrated by the discovery that the B chain of human PDGF is homologous to the transforming protein of simian sarcoma virus (SSV), the EGF (epidermal growth factor) receptor to erb B; the CSF (colony stimulating factor) receptor to fms; and the NGF (nerve growth factor) receptor to trk. In addition, growth factor receptors are often found amplified and/or overexpressed in cancer cells as exemplified by the observation that the EGF receptor is often found amplified or overexpressed in squamous cell carcinomas and glioblastomas. Similarly, amplification and overexpression of the met gene, encoding the HGF receptor, has been detected in stomach carcinomas.
Recently, a number of cDNAs have been identified that encode receptor tyrosine kinases. One such clone, referred to as DDR (discoidin domain receptor), was isolated from a breast carcinoma cDNA library (Johnson et al., 1993, Proc. Natl. Acad. Sci. USA, 90, 5677-57681) and is homologous to MCK-10. In addition, a mouse homologue of MCK-10 has recently been cloned and characterized (Yerlin, M. et al., 1993, Oncongene, 8:2731-2739).
The discovery of novel receptor tyrosine kinase receptors, whose expression is associated with proliferative diseases such as cancer, will provide opportunities for development of novel diagnostic reagents. In addition, the identification of aberrantly expressed receptor tyrosine kinases will lead to the development of therapeutic applications designed to inhibit the activity of that receptor, which may be useful for treatment of proliferative diseases such as cancer.